Conformational studies of the synthetic precursor-specific region of preproparathyroid hormone.

Rosenblatt, Michael; Beaudette, Norman V.; Fasman, Gerald D.

doi:10.1073/pnas.77.7.3983

Cited by 104 publications

(33 citation statements)

References 48 publications

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“…This is consistent with observations of Waterhous and Johnson (1994), shown in Table 2, and others (Rosenblatt et al, 1980;Zhong & Johnson, 1992;M.H. Hecht, pers.…”

Section: Conformational Switching: the Actions Of Denaturants And Alcsupporting

confidence: 82%

Principles of protein folding — A perspective from simple exact models

et al. 1995

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General principles of protein structure, stability, and folding kinetics have recently been explored in computer simulations of simple exact lattice models. These models represent protein chains at a rudimentary level, but they involve few parameters, approximations, or implicit biases, and they allow complete explorations of conformational and sequence spaces. Such simulations have resulted in testable predictions that are sometimes unanticipated: The folding code is mainly binary and delocalized throughout the amino acid sequence. The secondary and tertiary structures of a protein are specified mainly by the sequence of polar and nonpolar monomers. More specific interactions may refine the structure, rather than dominate the folding code. Simple exact models can account for the properties that characterize protein folding: two-state cooperativity, secondary and tertiary structures, and multistage folding kinetics-fast hydrophobic collapse followed by slower annealing. These studies suggest the possibility of creating "foldable" chain molecules other than proteins. The encoding of a unique compact chain conformation may not require amino acids; it may require only the ability to synthesize specific monomer sequences in which at least one monomer type is solvent-averse.Keywords: chain collapse; hydrophobic interactions; lattice models; protein conformations; protein folding; protein stabilityWe review the principles of protein structure, stability, and folding kinetics from the perspective of simple exact models. We focus on the "folding code''-how the tertiary structure and folding pathway of a protein are encoded in its amino acid sequence. Although native proteins are specific, compact, and often remarkably symmetrical structures, ordinary synthetic polymers in solution, glasses, or melts adopt large ensembles of more expanded conformations, with little intrachain organization. With simple exact models, we ask what are the fundamental causes of the differences between proteins and other polymers-What makes proteins special?One view of protein folding assumes that the "local" interactions among the near neighbors in the amino acid sequence, the interactions that form helices and turns, are the main determinants of protein structure. This assumption implies that isolated helices form early in the protein folding pathway and then assemble into the native tertiary structure (see Fig. 1). It is the premise behind the paradigm, primary + secondary -+ tertiary structure, that seeks computer algorithms to predict secondary structures from the sequence, and then to assemble them into the tertiary native structure.Here we review a simple model of an alternative view, its basis in experimental results, and its implications. We show how the nonlocal interactions that drive collapse processes in heteropolymers can give rise to protein structure, stability, and folding kinetics. This perspective is based on evidence that the folding code is not predominantly localized in short windows of the amino acid sequence. It...

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“…This is consistent with observations of Waterhous and Johnson (1994), shown in Table 2, and others (Rosenblatt et al, 1980;Zhong & Johnson, 1992;M.H. Hecht, pers.…”

Section: Conformational Switching: the Actions Of Denaturants And Alcsupporting

confidence: 82%

Principles of protein folding — A perspective from simple exact models

et al. 1995

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“…This is reminiscent of the conformations of the pre-pro-parathyroid hormone precursor peptide. The Chou-Fasman algorithm predicted two structures, one largely a-helical and the other rich in P-strands (52). Circular dichroism studies demonstrated that this peptide could adopt two distinct conformations under different solvent conditions.…”

Section: Methodsmentioning

confidence: 99%

Proposed three-dimensional structure for the cellular prion protein.

Huang

Gabriel²,

Baldwin³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

169

109

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Prion diseases are a group of neurodegenerative disorders in human and animals that seem to result from a conformatlonal change in the prion protein (PrP). Utilizing data obtained by circular dichroism and in spectroscopy, computational studies prdIe the tedi nal s ture of the cellular form of PrP (PrPC). A heuristic approach consistng of the prediction of so structures and of an evalnation of the pig of s y elements was used to search for plausible teriay strucures. After a series of experimental and theoretical ants were applied, four structural models of four-helix bundles emerged. A group of amino acids within the four predicted helices were Identified as important for tertiary interactions between helices. These amino acids could be essential for ma ining a stable tertiary suture of PrPC. Among four plausible s al models for PrPC, the X-bundle model seemed to correlate best with 5 of 11 known point mutations that segregate with the inherited prion diseases. These 5 mutions cluster around a central hydrophobic core in the X-bundle structure. Furthermore, these mutations occur at or near those amino acds which are predicted to e important for helix-helix interactions. The three-dimensonal structure of

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“…Secondary structure switching has been observed over a long period of time. 235,236,237,238 Recently, from a collection of such examples, a predictor of switch sequences was developed 239 and applied to myosin 240 in an effort to better understand the conformational changes in this molecule.…”

Section: Figure 8: Implications For the Protein Structural Hierarchymentioning

confidence: 99%

Intrinsically disordered protein

Dunker

Lawson

Brown

et al. 2001

Journal of Molecular Graphics and Modelling

2,133

2,085

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Proteins can exist in a trinity of structures: the ordered state, the molten globule and the random coil. Five examples follow which suggest that native protein structure can correspond to any of the three states (not just the ordered state) and that protein function can arise from any of the three states and their transitions. 1. In a process that likely mimics infection, fd phage converts from the ordered into the disordered molten globular state. 2. Nucleosome hyperacetylation is crucial to DNA replication and transcription; this chemical modification greatly increases the net negative charge of the nucleosome core particle. We propose that the increased charge imbalance promotes its conversion to a much less rigid form. 3. Clusterin contains an ordered domain and also a native molten globular region. The molten globular domain likely functions as a proteinaceous detergent for cell remodeling and removal of apoptotic debris. 4. In a critical signaling event, a helix in calcineurin becomes bound and surrounded by calmodulin, thereby turning on calcineurin's serine/threonine phosphatase activity.Locating the calcineurin helix within a region of disorder is essential for enabling calmodulin to surround its target upon binding. 5. Calsequestrin regulates calcium levels in the sarcoplasmic reticulum by binding about 50 ions/molecule. Disordered polyanion tails at the carboxy terminus bind many of these calcium ions, perhaps without adopting a unique structure. In addition to these examples, 16 more proteins with native disorder will be discussed. These disordered regions include molecular recognition domains, protein folding inhibitors, flexible linkers, entropic springs, entropic clocks and entropic bristles.Motivated by such examples of intrinsic disorder, we are studying the relationships between amino acid sequence and order/disorder, and from this information we are predicting intrinsic order/disorder from amino acid sequence.The sequence/structure relationships indicate that disorder is an encoded property, and the predictions strongly suggest that proteins in nature are much richer in intrinsic disorder than are those in the Protein Data Bank. Recent predictions on 29 genomes indicate that proteins from eucaryotes apparently have more intrinsic disorder than those from either bacteria or archaea, with typically > 30 % of eucaryotic proteins having disordered regions of length = 50 consecutive residues.

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Conformational studies of the synthetic precursor-specific region of preproparathyroid hormone.

Cited by 104 publications

References 48 publications

Principles of protein folding — A perspective from simple exact models

Principles of protein folding — A perspective from simple exact models

Proposed three-dimensional structure for the cellular prion protein.

Intrinsically disordered protein

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